The subject of the invention is metabolites of the products of formula I, and compounds of formula II and formula III below.
1. Field of the Invention
The present invention relates to [1,4]diazepino-[6,7,1-hi]indoles, and to those for the preparation of medicaments that enable treatment of affections which are amenable to therapy by a phosphodiesterase IV inhibitor. These medicaments are useful, in particular, as anti-inflammatories, anti-allergics, bronchodilators or anti-asthmatics and are devoid of digestive or cardiac side-effects.
2. Technological Background of the Invention
WO-A-9611690 describes [1,4]diazepino[6,7,1-hi]indoles, including in particular (3R)-N-(9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro[1,4]diazepino[6,7,1-hi]indol-3-yl)isonicotinamide. (which will be abbreviated to MPTDI in the text which follows).
The subject of the invention is metabolites of the products of formula I and of the products of formula II or III below.
In a first aspect, the invention relates to the metabolites of the products of formula (I): 
in which:
R is a lower alkyl or alkoxy;
A is aryl, nitrogen-containing heteroaryl or sulphur-containing heteroaryl, each optionally substituted with one to three groups independently chosen from halogen, lower alkyl, haloalkyl, lower alkoxy, hydroxyl, acetoxy, amino, t-butoxycarbonylamino, cycloalkylcarbonylamino or acetamido; of their racemic forms, of their isomers having a configuration which is determined by the carbon at the 3-position of the diazepinoindol-4-one ring, and of their pharmacologically acceptable salts.
Preferably, R is a methyl group.
Preferably, the asymmetric carbon has the R configuration.
Preferably, the product of formula I is the product N-(9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)isonicotinamide, advantageously the configuration is 3R.
This term  less than  less than metabolite greater than  greater than  covers these products derived from biodegradation by a mammal, in particular humans, of the said products of formula I.
The, preferred metabolites are those which are oxidized and/or hydroxylated, on the substituents and/or the rings and/or heterocycles.
In particular, the invention relates to the metabolites corresponding to the derivatives which are hydroxylated on the pyrrolidine or 1-phenylbenzodiazepine ring.
Advantageously, the products are those in which A is pyridyl, optionally N-oxidized.
In a second aspect, the invention relates to the diazepinoindoles of formula (II) 
in which:
Z is a lower alkyl or alkoxy;
A is aryl, nitrogen-containing heteroaryl or sulphur-containing heteroaryl, each optionally substituted with one to three groups independently chosen from halogen, lower alkyl, haloalkyl, lower alkoxy, hydroxyl, acetoxy, amino, t-butoxycarbonylamino, cycloalkylcarbonylamino or acetamido, the N-oxide or S-oxide forms;
Y is hydroxyl or lower alkoxy;
n is 1 or 2.
of their racemic forms, of their isomers having a configuration which is determined by the carbon at the 3-position of the diazepinoindol-4-one ring, and of their pharmacologically acceptable salts.
Preferably, Y is hydroxyl or methoxy.
The phenyl is preferably substituted at the para-position, advantageously with a hydroxyl.
Advantageously, the products are those in which A is pyridyl, optionally N-oxidized.
Among the diazepinoindoles of formula (II), those in which the asymmetric carbon atom at the alpha-position with respect to the carbonyl of the diazepine ring has the absolute configuration (R), are preferred.
Examples of such products are reproduced below: 
In a third aspect, the invention relates to the diazepinoindoles of formula (III) 
in which:
Zxe2x80x2 is hydroxymethyl, formyl, carboxylic acid in its free form, salified, esterified or amidated, hydroxymethyl whose hydroxyl group is esterified;
Axe2x80x2 is aryl, nitrogen-containing heteroaryl or sulphur-containing heteroaryl, each optionally substituted with one to three groups independently chosen from halogen, lower alkyl, haloalkyl, lower alkoxy, hydroxyl, acetoxy, amino, t-butoxycarbonylamino, cycloalkylcarbonylamino or acetamido, the N-oxide or S-oxide forms;
Yxe2x80x2 is hydroxyl or lower alkoxy;
nxe2x80x2 is 0, 1 or 2.
of their racemic forms, of their isomers having a configuration which is determined by the carbon at the 3-position of the diazepinoindol-4-one ring, and of their pharmacologically acceptable salts.
Preferably, Zxe2x80x2 is chosen from the group consisting of hydroxymethyl; formyl; COOH; CONH2, COOD where D is a lower alkyl, optionally hydroxylated; xe2x80x94CH2xe2x80x94Oxe2x80x94C(O)xe2x80x94E where E is a lower alkyl, an aryl, cycloalkyl, or pyridyl.
Preferably, Yxe2x80x2 is hydroxyl or methoxy.
The phenyl is preferably substituted at the para-position, advantageously with a hydroxyl. Among the diazepinoindoles of formula (III), those in which the asymmetric carbon atom at the alpha-position with respect to the carbonyl of the diazepine ring has the absolute configuration (R), are preferred.
Advantageously, the products are those in which Axe2x80x2 is pyridyl, optionally N-oxidized.
Examples of such products are reproduced below: 
In the foregoing as well as hereinafter:
aryl is understood to mean a phenyl or naphthyl group;
nitrogen- or sulphur-containing heteroaryl is understood to mean an unsaturated monocyclic or polycyclic group containing at least one nitrogen or sulphur atom, respectively, and preferably these heterocycles may be four- to seven-membered heteromonocyclic groups containing from 1 to 4 heteroatoms, or unsaturated fused heterocyclic groups containing from 1 to 4 heteroatom; the heteroaryl group may be methylated or ethylated on a positively charged nitrogen;
halogen is understood to mean fluorine, chlorine, bromine or iodine;
lower alkyl is understood to mean linear or branched alkyl groups containing from one to four carbon atoms;
cycloalkyl is understood to mean cyclopropyl, cyclobutyl and cyclopentyl groups;
lower alkoxy is understood to mean an O-alkyl group in which the alkyl group is a lower alkyl as defined above;
haloalkyl is understood to mean a mono-, di- or trihaloalkyl containing from 1 to 4 carbon atoms.
A review of salts which are acceptable in pharmacy will be found in J. Pharm. Sci., 1977, 66, 1-19. However, pharmacologically acceptable salt of a compound of formula (I) possessing a basic portion is understood to mean the addition salts of the compounds of formula (I) which are formed from nontoxic inorganic or organic acids such as, for example, the salts of hydrobromic, hydrochloric, sulphuric, sulphamic, phosphoric, nitric, acetic, propionic, succinic, glycolic, stearic, lactic, malic, tartaric, citric, mucic, ascorbic, pamoic, maleic, hydroxymaleic, phenylacetic, glutamic, benzoic, salicylic, sulphanilic, acetoxybenzoic, fumaric, toluenesulphonic, ethanedisulphonic, oxalic, isethionic and the like, acids. The various quaternary ammonium salts of the derivatives (I) are also included in this category of the compounds of the invention. And pharmacologically acceptable salt of a compound of formula (I) possessing an acidic portion is understood to mean the commonplace salts of the compounds of formula (I) which are formed from nontoxic inorganic or organic bases such as, for example, alkali metal and alkaline-earth metal hydroxides (lithium, sodium, potassium, magnesium and calcium hydroxides), amines (dibenzylethylenediamine, trimethylamine, piperidine, pyrrolidine, benzylamine and the like) or alternatively quaternary ammonium hydroxides such as tetramethylammonium hydroxide.
The invention also relates to the above products as a medicament, and in particular for combating inflammatory diseases, allergic diseases and bronchoconstriction, or which is useful in the treatment of asthma, characterized in that it comprises a diazepinoindole according to the invention, in a pharmaceutical dosage form which is suited to the disease to be treated. The invention also relates to the use of the above products for the preparation of the above-mentioned medicaments.
The compounds according to the invention may be synthesized by conventional routes from compounds of formula I as described in Application WO-A-9611690, by biological routes or by chemical synthesis.